Journal of Clinical Medicine Review General Overview of Nontuberculous Mycobacteria Opportunistic Pathogens: Mycobacterium avium and Mycobacterium abscessus Kimberly To 1, Ruoqiong Cao 2, Aram Yegiazaryan 1 , James Owens 2 and Vishwanath Venketaraman 2,* 1 Graduate College of Biomedical Sciences, Western University of Health Sciences, Pomona, CA 91766-1854, USA; [email protected] (K.T.); [email protected] (A.Y.) 2 Department of Basic Medical Sciences, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766-1854, USA; [email protected] (R.C.); [email protected] (J.O.) * Correspondence: [email protected]; Tel.: +1-909-706-3736 Received: 5 July 2020; Accepted: 4 August 2020; Published: 6 August 2020 Abstract: Nontuberculous mycobacteria (NTM) are emerging human pathogens, causing a wide range of clinical diseases affecting individuals who are immunocompromised and who have underlying health conditions. NTM are ubiquitous in the environment, with certain species causing opportunistic infection in humans, including Mycobacterium avium and Mycobacterium abscessus. The incidence and prevalence of NTM infections are rising globally, especially in developed countries with declining incidence rates of M. tuberculosis infection. Mycobacterium avium, a slow-growing mycobacterium, is associated with Mycobacterium avium complex (MAC) infections that can cause chronic pulmonary disease, disseminated disease, as well as lymphadenitis. M. abscessus infections are considered one of the most antibiotic-resistant mycobacteria and are associated with pulmonary disease, especially cystic fibrosis, as well as contaminated traumatic skin wounds, postsurgical soft tissue infections, and healthcare-associated infections (HAI). Clinical manifestations of diseases depend on the interaction of the host’s immune response and the specific mycobacterial species. This review will give a general overview of the general characteristics, vulnerable populations most at risk, pathogenesis, treatment, and prevention for infections caused by Mycobacterium avium, in the context of MAC, and M. abscessus. Keywords: Nontuberculous mycobacteria; Mycobacterium avium; Mycobacterium abscessus; Mycobacterium avium complex; M. tuberculosis; bronchiectasis; lymphadenitis; immunocompromised; Azithromycin; macrolides 1. Introduction Nontuberculous mycobacteria (NTM) are a group of bacteria under the genus Mycobacterium, which includes Mycobacterium tuberculosis, comprising more than 172 species with many unique virulence characteristics (see Table1 for examples of pathogenic species). NTM are found ubiquitously in the environment and present in water sources, soil, domestic and wild animals, and milk and food produce. NTM are opportunistic pathogens to animals and humans, including fish and poultry [1]. As opposed to tuberculosis caused by M. tuberculosis infection, NTM infection reporting is not mandatory; therefore, the incidence and prevalence of the different species of NTM are difficult to determine. However, the prevalence of NTM infection is growing in the United States, Europe, and other developed countries in the Western world. The increased occurrences of NTM infections are associated with declining tuberculosis rates in areas of higher socioeconomic standards. In a systematic review of J. Clin. Med. 2020, 9, 2541; doi:10.3390/jcm9082541 www.mdpi.com/journal/jcm J. Clin. Med. 2020, 9, 2541 2 of 25 22 studies between 1946 and 2014, most studies overall found an 81% declining tuberculosis (TB) incidence rate, while NTM disease rose by 94% in almost every geographic area [2]. Their importance is due to their growing emergence as human pathogens causing opportunistic infections in severely immune-compromised individuals, people with congenital or acquired anatomical lung diseases, and healthcare-associated infections [1]. However, there is also a noted increased incidence in NTM disease in people who are not immunocompromised and without any preexisting lung diseases. One study found that 18% of MAC pulmonary infections were from people without predisposing conditions, similar to the other literature on this group [3]. Another study found that, for this group, they accounted for 20% of all clinical NTM infections; they also tended to have a delayed diagnosis and a high recurrence rate [4]. Table 1. Human pathogenic mycobacteria. Human Pathogenic Mycobacteria Mycobacterium Non-Tuberculous Mycobacteria Leprotic Group Tuberculosis Complex Rapidly Growing Slow Growing Mycobacteria M. avium complex M. abscessus group M. tuberculosis -M. avium -M. abscessus M. bovis -M. chimaera -M. bolletii M. africanum -M. intracellulare -M. massiliense M. canettii M. haemophilum M. fortuitum group M. caprae M. gordonae M. leprae Species -M. fortuitum M. pinnipedii M. kansasii M. lepromatosis -M. peregrinum M. orygis M. simiae -M. porcinum M. microti M. marinum M. smegmatis M. mungi M. malmoense M. vaccae M. suricattae M. xenopi M. mucogenicum M. ulcerans NTM infection mainly presents four distinct clinical diseases in humans: (1) chronic pulmonary disease; (2) disseminated disease in severely immunocompromised patients; (3) skin and soft tissue infection; and (4) superficial lymphadenitis, especially cervical lymphadenitis in children. Pulmonary disease accounts for 80–90% of NTM-associated diseases [5]. The most common NTM species causing human disease are the slow-growing mycobacteria Mycobacterium avium in the Mycobacterium avium complex (MAC), the rapid-growing M. abscessus, and M. kansasii. In this review article, we will discuss the vulnerable populations affected by these opportunistic infections, the pathogenesis, treatment, and prevention of infections caused by Mycobacterium avium, with a focus on the Mycobacterium avium complex (MAC), as well as infections caused by Mycobacterium abscessus. 2. Mycobacterium avium 2.1. General Characteristics Mycobacterium avium complex (MAC) infections are caused by a group of mycobacteria consisting of M. avium, M. intracellulare, and the newly described mycobacterium species, Mycobacterium chimaera, which are all acid-fast slow-growing mycobacteria, classified as non-chromogens in group III of the Runyon classification of NTM. MAC initially included only M. avium and M. intracellulare, but with new genetic sequencing technology, phenotypic and genotypic tests have identified additional species. To date, MAC contains nine species of slow-growing mycobacteria: M. avium, M. intracellulare, M. chimaera, M. colombiense, M. marseillense, M. timonense, M. boucherdurhonense, M. vulneris, M. arosiense, and a small group of unclassified, “MAC others” [6]. Recently, M. chimaera was implicated in worldwide outbreaks in five countries including the USA, Europe, and Australia, due to contaminated heater–cooler unit water tanks in patients that underwent open-heart surgery, such as coronary artery J. Clin. Med. 2020, 9, 2541 3 of 25 bypass grafting [7]. Investigations found the culprit was contamination from the Stöckert 3T heating and cooling unit manufactured by LivaNova PLC in London [8]. The sequence of the 16-23S internal spacer (ITS) region of M. chimera corresponds to the sequevar MAC-A compared to the M. intracellulare sequevar MIN-A (DSMZ 43223) by 20 nucleotide (nt) mismatches. Additionally, the 16S rRNA gene sequence between the two species only has a 1 nt mismatch. Since the sequence of 16S rDNA is considered the approved standard for identifying NTM species, M. chimaera is usually misreported as M. intracellulare [9,10]. Traditionally, standard molecular genetic tools in clinical microbiology laboratories did not differentiate MAC members and only gave a rough classification of M. avium, M. intracelllulare, or MAC as a whole since treatment is the same for all MAC species. Detailed genotyping of MAC species was limited to specialized research laboratories that can perform PCR of several genes such as rpo or hsp65 and ITS [11]. However, due to these recent outbreaks associated with cardiac surgery, clinical laboratories are now mandated to differentiate M. chimaera from other MAC species [7]. The most clinically significant organism for human disease within MAC is Mycobacterium avium, with four distinct subspecies. This group of bacteria ranges from environmental bacteria that can cause opportunistic infections in immunosuppressed individuals to pathogens for birds and other animals. The characteristics of the four distinct species of M. avium are discussed. M. avium subsp. Hominissus (MAH) is an opportunistic environmental pathogen for humans, swine, and other animals that are found in soil and water. Drinking water and tap aerosols are considered the primary sources for infection in humans. MAH is clinically the most relevant organism within MAC for humans and a major pathogen for individuals with deficient T cell immunity. Before the development of antiviral therapy, in the early years of the Acquired Immunodeficiency Syndrome (AIDS) epidemic, 20–50% of severely immunocompromised AIDS patients had disseminated infections with MAC organisms, now identified as MAH infections [12]. MAH is still a threat to newly diagnosed HIV patients and individuals with no access to antiviral therapy or for those that antiviral therapy is ineffective [13]. In immunocompromised individuals, MAH can cause pulmonary infections, cervical infections, mainly in children, and soft tissue infections. M. avium subsp. Paratuberculosis (MAP) is a widely known pathogen that causes paratuberculosis, also known